Ultrasound-triggered drug delivery using stimuli-responsive hydrogels refers to the process of using ultrasound energy for inducing drug release from hydrogels that are sensitive to acoustic stimuli. This method of approach is one of many stimuli-responsive drug delivery-based systems that has gained traction in recent years due to its demonstration of localization and specificity of disease treatment. Although recent developments in this field highlight its potential in treating certain diseases such as COVID-19, there remain many major challenges that need to be addressed and overcome before more related biomedical applications are clinically translated into standard of care.
Types of Hydrogels Used in Drug Delivery Systems
Traditional Hydrogels
Hydrogels are three dimensional structures consisting of hydrophilic polymers (i.e., polymers, colloids, etc.) that form networks through cross-linking processes. The macromolecules involved in the formation of hydrogels are able to absorb and retain large amounts of water and other aqueous substances. Since its discovery in 1960, hydrogels have become a crucial component in biomedical research and applications. A few examples of hydrogel use include organ regeneration, wound healing, and drug delivery. Hydrogels are generally classified based on the following characteristics: material, crosslinking mechanism, physical structure, electric charge, and response to stimuli. Synthesis of hydrogels are developed from a combination or isolated forms of natural and synthetic polymers. The main examples of natural polymers used to derive hydrogels include polysaccharides, polypeptides, and polynucleotides. Several known examples of synthetic polymeric constituents include poly (vinyl alcohol) (PVA), poly (acrylic acid) (PAA), and poly (2-hydroxyethyl methacrylate) (PHEMA). The crosslinking mechanism of the hydrophilic macromolecules are driven by covalent bonding, resulting in a physical- or chemical-type hydrogel. Physical hydrogels contain reversible matrices of hydrogen and non-covalent bonds, while chemical hydrogels are composed of irreversible matrices that are molecularly held together by covalent bonds. Used as another parameter in characterizing gels, electric charge (also referred to as ionic character) describes the ability of the macromolecules to drive swelling behavior. Hydrogels classified based on this property fall under three main categories: cationic, anionic, and amphoteric. Bawa et al. demonstrated that cationic gels swell in acidic environments but remain condensed in basic environments.
Smart Hydrogel Polymers
Since traditional hydrogels were able to encapsulate and carry materials, research into drug-loaded hydrogels began to expand in the field of drug delivery. Dubbed as "smart hydrogels" or "stimuli-responsive hydrogels", these gels are able to dynamically respond to external or internal stimuli in addition to possessing similar swelling-deswelling properties of traditional hydrogels. Various examples of external stimuli that have been used to control smart hydrogels in drug delivery systems include temperature, pH, light, ultrasound, and enzymes. Additional considerations in designing smart hydrogels involve fundamental understanding of bond strength, molecular weight, degree of polymerization, polymer structure, and molecular assembly. The bond strength describes the cross-linking strength of the hydrogel, which is considered in designing drug release mechanisms of hydrogel-based platforms. Scientific understanding of the molecular weight of gels is taken into account when loading drugs of increasing weight. Similar to conventional hydrogels, the polymeric chain (or backbone) of the smart hydrogels is derived from polysaccharides, polypeptides, and polynucleotides. Examples of natural polymers include alginate, chitosan, cellulose, gelatin, fibrin, and collagen. Hydrogel size and type are the two main properties considered in designing hydrogels when seeking the optimal delivery route for drug administration. Various examples of hydrogel type designs include nanoparticles, nanogels, and microgels. For example, El-Sherbiny et al. proposed gelatin-based hydrogel nanoparticles that were stimulated by magnetic forces. Other variables considered in hydrogel design include safety, biodegradability, drug loading capacity, and on-demand control of drug release [23]. The main safety concerns in formulating hydrogels include bacterial infection and biocompatibility. The final parameter considered in developing hydrogels for drug delivery systems revolve around the embedded payload within the hydrogel. Cells, proteins, and therapeutic drugs are the main payloads used in hydrogel-based drug delivery platforms. In one example of payload use, Jiang et al. demonstrated the stimulated release of gallic acid from chitin-based hydrogel via ultrasound induction.
Use of Ultrasound for Drug Therapy
General Overview of Ultrasound According to the Moyano et al., ultrasound refers to vibrational mechanical waves with frequencies greater than 20 kilohertz (kHz). Ultrasound is traditionally used for imaging, monitoring, and diagnosing a broad range of conditions in the medical field. Various examples of ultrasound modalities include Doppler ultrasound, focused ultrasound, and echocardiography. The key component of using most ultrasound devices is a transducer that consists of an array of piezoelectric crystals. The atoms within these crystals vibrate under electrical current stimulation, converting this electrical energy into mechanical, in this case, high acoustic or ultrasonic energy. When the sonicating transducer is directed at the human body, the resulting sound pressure waves produced by the transducer will pass through the dermal layer and reach the tissue where the waves are reflected (or echoed) back to the transducer and converted back into electrical signals for image reconstruction. Tissue characteristics such as density affect the intensity of the reflected sound waves. Other parameters such as beam frequency, equipment components, and imaging settings contribute towards the resolution of the ultrasound application. Ultrasound has also been used for therapeutic purposes because it is non-invasiveness, able to provide deeper tissue penetration, and safely localize application of acoustic energy.
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